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Comparative Oncogenomics for Peripheral Nerve Sheath Cancer Gene Discovery

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Annual rept. 1 Jun 2014-31 May 2015

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We have developed a robust transgenic mouse model P0-GGF 3 mice in which overexpression of the growth factor neuregulin-1 NRG1 results in the reproducible development of plexiform neurofibromas which subsequently progress to become MPNSTs. We hypothesized that comprehensively characterizing alterations in the genomes and gene expression profiles of peripheral nerve sheath tumors arising in our P0- GGF 3 mouse model will identify candidate driver genes mediating plexiform neurofibroma pathogenesis and neurofibroma-MPNST progression, thereby identifying new therapeutic targets in the equivalent human tumors. To test this overarching hypothesis, we are using a comprehensive multi-tiered process to identify candidate driver mutations in P0-GGF 3 neurofibromas and MPNSTs, establish gene signatures defining distinct tumor subtypes and functionally test the role of selected driver mutations characteristic of specific subtypes. Potential driver mutations within relatively large regions of chromosomal gain or loss will be identified using high density array comparative genomic hybridization aCGH and cross-species comparisons of this data with aCGH findings from human neurofibromas and MPNSTs. Smaller mutations missense mutations, nonsense mutations, small indels and fusion events will be identified using a combination of transcriptome RNA-Seq and exome sequencing in these same murine tumors. The contribution of selected candidate driver mutations characteristic of specific tumor subtypes will be validated by manipulating the function of these genes and examining the effect this has in vivo, using orthotopically allografted tumor cells, and a variety of in vitro functional assays. We will validate the relevance of these mutated mouse genes in human neurofibromas and MPNSTs by determining whether these same genes are mutated in human tumors.

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  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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